Abstract

The neurobiological underpinnings of substance use disorders (SUDs) involve complex alterations in synaptic plasticity within the mesolimbic dopamine system, particularly within the ventral tegmental area (VTA). While dopamine neurons in the VTA are extensively studied in addiction research, less attention has been given to the plasticity exhibited by VTA GABAergic neurons, despite their established regulatory role in modulating dopamine cell activity. Building upon the ground-breaking work of Bocklisch et al. (2013), we investigated the plasticity at the GABAergic to VTA GABA neuron (VTA GABA-to-GABA) synapse utilizing whole-cell electrophysiology in GAD67 GFP knock-in mice. Our findings revealed an exceptionally rare duo-plasticity response at this specific synapse, where postsynaptic VTA GABA neurons undergo either inhibitory long-term potentiation (iLTP) or inhibitory long-term depression (iLTD) when reacting to the same low-frequency 5Hz stimulation. Evidence from paired pulse ratio (PPR) and co-efficient of variation (1/CV2) analyses supports a presynaptic mechanism for both types of plasticity. While the induction of iLTP relies partially on N-methyl-D-aspartic acid receptor (NMDAR) activation, the iLTD is GABAB receptor (GABABR)-dependent. Dissatisfied with the finding that the observed iLTP exhibits only partial reliance on NMDAR, we embarked on a quest to delve deeper into the molecular mechanisms governing this type of plasticity. Specifically, we investigated the potential engagement of the neuropeptide cholecystokinin (CCK) and the nitric oxide (NO) pathway, both of which have been implicated in LTP discovered in various brain regions including the VTA. Nevertheless, neither CCK nor the NO pathway appears to be essential for the induction of iLTP. To elucidate the mystery behind the duo-plasticity response, we employed an optogenetic approach in VGAT-Cre mice to target inhibitory inputs from the lateral hypothalamus (LH), the rostromedial tegmental nucleus (RMTg) and the local VTA interneurons. We exclusively observed iLTP at both the LH and RMTg to VTA GABA pathways, while the local VTA interneuron to VTA GABA pathway exhibited solely iLTD, suggesting the duo-plasticity response is input-specific. More importantly, we explored how different classes of addictive drugs such as ethanol, cocaine and opioids might modify the duo-plasticity response at the VTA GABA-to-GABA synapse. Chronic exposure to both ethanol and cocaine eliminated iLTD but left iLTP intact. Surprisingly, chronic morphine exposure displayed no effect on either the iLTP or the iLTD despite dense presence of µ-opioid receptors in the inhibitory afferents to VTA GABA neurons. Altogether, the above findings shed light on the molecular mechanisms underlying synaptic plasticity in inhibitory synapses onto VTA GABA cells, enhancing our understanding of VTA neural circuitry and its implications for addiction pathology and treatment.

Degree

PhD

College and Department

Life Sciences; Physiology and Developmental Biology

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2024-03-28

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd13531

Keywords

GABA, long-term depression, long-term potentiation, addiction, ethanol, cocaine, opioids

Language

english

Download

Included in

Life Sciences Commons

Share

COinS